Human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, causes serious lower respiratory tract infections in young children, the elderly and immunocompromised patients. Development of a vaccine against hMPV has progressed slowly and no specific therapy is currently available. The mechanisms of hMPV-mediated lung pathology and clinical disease are not fully understood, but experimental evidence suggests that T cells, particularly the CD4+ compartment, play a central role in the immunopathogenesis of hMPV infections. Based on preliminary data from our group, we will test the hypothesis that lung plasmacytoid dendritic cells (pDC), critical immune cells in mediating antiviral response, play a major role in controlling hMPV-induced lung inflammation. Funding from this R03 grant will be used to generate critical data in support of the hypotheses that pDC regulate pulmonary inflammation in hMPV infection by the induction of regulatory T cells and IL-12p40 production. The work that we propose in this grant includes investigations in a well established experimental mouse model of hMPV infection. Accomplishment of the proposed aims will generate the base for additional mechanistic studies that I will pursue through an NIH R01 application where overall objective will be focused on defining the cellular and molecular mechanisms by which pDC regulate lung pathogenesis in hMPV infection. Understanding the mechanisms that regulate hMPV- induced inflammation in the lung is important clinically for the development of new treatment strategies or novel vaccines for hMPV infection. PUBLIC HEALTH RELEVANCE: Human metapneumovirus (hMPV), a newly-recognized member of the Paramyxoviridae family, is one of the major etiologic agents of lower respiratory tract infections in infants and young children. We have shown that plasmacytoid dendritic cells (pDC) regulate pulmonary inflammation in a mouse model of hMPV infection. In this pilot grant proposal we will investigate the mechanisms by which lung pDC control inflammatory responses during hMPV infection with the long long-term goal of developing new strategies to boost antiviral immunity and long-lasting protection against hMPV and other respiratory viral pathogens that cause significant airway morbidity.